The use of transition-state analogs as potent and specific inhibitors of critical enzymes involved in regulation of cell growth should offer a means to study the exact nature of the control processes. In addition, such new drugs might prove to be effective in cancer chemotherapy. A series of investigations are proposed in which selected enzymes are considered in terms of their chemical mechanism of action, leading to the design of a transition-state analog inhibitor specific for each particular enzyme. The reactions considered in this application are of two general types, namely alkylation and phosphorylation. In the former group are enzymes (S-adenosylmethionine-dependent methylases, B12-dependent methionine synthetase, and spermidine synthase) involved in the biosynthesis and utilization of methionine. These reactions lead to methylated macromolecules (RNA, DNA, histones, etc.), and to the polyamines, both critical elements in cellular proliferation. In the second group of enzymes (glutamine, asparagine, and folatepolyglutamate synthetases, in addition to c-AMP-dependent protein kinases) phosphorylation of acids or alcohols lead to active intermediates of amide synthesis, and modified macromolecules respectively. The amides, glutamine, asparagine, and the folatepolyglutamates, are all intimately associated with nucleic acid synthesis, whereas the protein kinases are involved in hormone-induced phosphorylation of membrane proteins. Syntheses are described for transition-state analog inhibitors of the group of enzymes outlined above. Biological testing in a series of cell-free enzyme systems, in addition to selected cell culture systems, is also described.